AU2014228986A1

AU2014228986A1 - Method for non-toxic treatment for drug withdrawal

Info

Publication number: AU2014228986A1
Application number: AU2014228986A
Authority: AU
Inventors: Lawrence Friedhoff
Original assignee: DemeRx Inc
Current assignee: DemeRx Inc
Priority date: 2013-03-15
Filing date: 2014-03-14
Publication date: 2015-10-29
Also published as: EA201591679A1; CA2942511A1; KR20150130461A; US20160271139A1; JP2016514679A; AR095338A1; EP2968355A4; BR112015022465A2; EP2968355A2; ZA201507514B; US20140288056A1; CN105307658A; CA2942638A1; WO2014143201A1; US20150045350A1; WO2014144508A2; US9744174B2; TW201505634A; HK1220381A1

Description

WO 2014/144508 PCT/US2014/028946 METHOD FOR NONTOXIC TREATMENT FOR DRUG WITHDRAWAL BACKGROIUND 00011 The disclosure relates to the treatment of drug w withdrawal symptoms. 100021 W withdraw fromi drug depedence is characterized by dramatic and traumatic symptoms, I liding sweating racine heat palpitations, muscle tension, tightness in the chest, difficulty breathing, tior, nausea, vomiting, diarrhea. grand mal seizures, heart attacks. strokes, hallucinations and deiium tremens (DTs). Numerous treatments have been developed in attempts to ameliorate such symptoms. [00031 lbogaine has been used as a botanical preparation from the root bark of iboga tabernathe for over 100 years both as a crude preparation and as semisynthetic ibogaine. which was marketed in France until about 1970. Observations in the 1970's suggested that ibogaine in higher doses was useful as a treatment for addiction. The use of ibogaine as a treatment for addiction was controversial because higher doses caused hallucinations and, in spite of many anecdotal reports of sticking efficacy, no double-blind, placebo-controlled trials supported the efficacy of ibogaine as a treatniat for withdrawal or addiction. 100041 'US Patent No. 6,348,456 discloses highly purified noribogaine and teaches that it should be provided at dosages from about 0.01 to about 100 mg per kg body weight per day. [0005] More recently, the pharmacokinetics and metabolism of ibogaine was evaluated and it was found that the psychotomirnetic effects correlated with blood levels of ibogaine, while the anti-addictive etects correlated with blood levels of noribogaine. the only tabolit Of hogaine fnd i in humans, dogs. rats and nonkey s. These experiments were ioNed uip with aninal studies of noribogaine in various addiction models, which demonstrated hat noribogaine signifIcantly reduced drug-seeking behavior and had no activity in an evaluation of psychtomimetic effects in an animal model Noribogaine is now being developed as a treatment tor he symptoms of drug addiction and has shown to be effective in animal models of addiction to alcohol, cocaine and opiate dependence. [00061 Durin pre-cliical toxicity studies in various animal species. it was found that high doses of norihogaine can cause convulsions and other CNS-related clinical signs respirtory arrest and death. iv en the signs of eficacy that norihogainc has shown, there is a need or a 1 WO 2014/144508 PCT/US2014/028946 method to administer no 1 , : in dosaes at pnovide e,,:iiey Without leading to any signif icant deleterious clinical signs, SUM MARY 10007] The disclosure provides a method to administer noribogac to a human patient having drug addiction in dosages that provide efficacy without leading to any significant deleterious clinical signs. Such dosages provide maximum serum concentrations (Cm,) of, noribogaine of less than about 2000 ng/mL, while maintaining efficacious average noribogaine serum levels of between about 100-2000 ng/mL (AUC/T). [00081 One embodiment of disclosure provides a method for creating withdrawal symptoms in a patient suffering Irom withdrawal from addiction io a substance comparing administering to he patient a dosage of noogaie thaat provides aC o noribogaine of less than about 1980 ng/mL. serurn and an average A UC/24 hr of abmut 1, 100 g/mL [00091 Also provided, in one embodiment, is a method for treating withdrawal symptoms in a patient suffering from withdrawal from addiction to a substance comprising administering to the patient a dosage of noribogaine that provides a , of noribogaine of less than about 1800 ngmL serum and an AMY/24 hr of about 1000 ng/mL-. [00101 Also provided, in one embodinent, is a method for treating wi thrawal symptoms in a patient suffering from withdrawal fiaddiction to a substance comprising administering to the patient a dosage of noribogaine that provides a Cm, of noribogaine of less than about 1620 ng/mL serum and an AUC/24 hr of about 900 ng/mL [00111 Also provided, in one embodiment is a method for treating withdrawal symptoms in a patient ing fcrn withdrawal from addiction to a substance comprising administering to the patient a dosage of rnoriogaine that provides a C,. of ntribogaine ofless than about 1440 ng/mL serum and an A UC/24 hr of about 800 Au/mL [0012 AlsiXo provided, in one embodiment, is a imiethod for treating wiuthdrawxal symptoms tn a patet suffering fror withdrawal from addiction to a substance comprising administering to the patient a dosage of noribogaine that provides a C, of noribogaine of less than about 1260 ng/mL serum and an AUC/24 hr of about 700 ng/mL 2 WO 2014/144508 PCT/US2014/028946 100131 Also provided in one embodiment, is a method fr treating withdiawal symptoms in a patient suffring W from withdraw ! fror addiction to a substaice copirising administering to the patient a dosage ot noribogan thPat provides a Cm, of noriboaine of less than about 1400 ng/L serum and an AU C 24; hr of from about 600 P gL [00141 Also prov ided in one embodiment is a method for treating withdrawal syamntos in a patient suering rom w ithdrw al from addiction to a substance comprisi adminstering tthe paticta dosage of noribogaine that provides a (,,, of noribogaine of less than about 900 ng/ml, serum and an A UC/24 hr of about 500 ng/mL. [0015] Also provided, in one emboiment, is a method for treating withdrawal symptoms in a patient suffering from withdrawal front addiction to a substance comprising administering to the patient a dosage of noribogaine that provides a ,,x of noribogaine of less than about 720 nlg/Lrn serum and an AUC/24 hr of about 400 ng/muL [00161 lso provided. in one embodiment, is a method for treating withdrawa symptoms in a patient suffering from withdrawaol from addiction to a substance comprising administering to the patient a dosage of norbogaine that provides a C,,, of noribogaine of less than about 540 ng/mL serum and an AUC/24 hr of about 300 ng/mL 100171 Also provided, in oei embodiment, is a method for treating withdrawal symptoms in a patient suffering from withdrawal fron addiction to a substance comprising admninitering to the paint a dosage of noribogaine that provides a Cm,, of noribogaine of less than abot 360 ng/mL serum and an AUC/24 hr of about 200 ng/mL 10018] Also provided, in one embodiment, is a method for treating vithdrawai symptoms in a patient suffering from withdrawal from addiction to a substance comprising administering to the patient a dosage of norbogaine that prove ides a Cma ofnoribogaine of less than about 180 ng/mL. serun and an AUC/24 hr of about 100 ng/mL 100191 Also provided, in one enbodinent. is a method fb treating withdrawl symptoms in a patient suffering rom iMtdrawal from addiction to a substanceomprising admnistering to the patient a dosage of noribogaine from about i 00 ig to about 600 rmg at intervals of about 24 hours. 3 WO 2014/144508 PCT/US2014/028946 100201 in soime enihodiments, the patient is administered a dosage of noriboga ne from about 100 mg to about 500 n at intervaIs of about 24 hous In snoe einbodin-nts, the patient is administered a dosage of noribogain cron about 100 im to about 400 mge at nterv als of abOut 24 hoors. In some embodiments, the patient is administered a dosage of noribogaine from about 100 rmg to about 300 ng at inervais of about 24 hours. In sonte embodiments, the patient is administered a dosage of noribogaine from about 100 mg to about 200 mg at intervals of about 24 hours. 100211 Also pro ided, in one embodiment. is a mthod fi treatn withdr awl symptoms in a patten suffeing fromi withdrawa al frorm addiction to a substance comprising administeng to the patient a dsage of noribogaine from about 200 mg to about (00 tug at intervas of about 24 hours. 100221 In some embodiments, the patient is administered a dosage of noribogaine from about 200 mg to about 500 ing at intervals of about 24 hours In some embodhments, the patient is administered a dosage of noribogaine from about 200 rmg to about 400 mg at intervals of about 24 hours, in some embodiments the patient is administered a dosage ot noribogaine from about 200 mag to about 300 mog at intervals of about 24 hours. 100231 Also provided, in one embodiment, is a method for treating withdrawal synptons in a patient suffering from withdrawal from addiction to a substance comprising administering to the patient a dosage of noribogaine frorn about 300 mng to about 600 mg at intervals of about 24 hours. 100241 In soie embodiments. the patient is administered a dosagc of noribogaine from about 300 mg to about 500 mg at intervals of about 24 hours. In some enibodiments. the patient is administered a dosage of noribogaine from about 300 mg to about 400 mg at intervals of about 24 hours, In some embodiments each patient is admtiristered from about 400 mg to about 500 mg at intervals of about 24 hours. [00251 Also provided, in one embodiment, is a method fio treating withdranal symptoms in a patient suffering from withdraw al from addiction to a substance comprising adninistering to the patient a dosage of noribogae from about 500 mg to about 600 mg at iner als of about 24 hous. BRIEF DESCRIPTION OF THE FIGURES 4 WO 2014/144508 PCT/US2014/028946 [0026] FIG. I represents iean nor-bogane concentration-ine profiles after single oral dosing wih 3, 10, 30 or 60 mg doses. Inset: Indiv idal concentration-time profiles for 0-1 2 h1 after a 10 mg dose. [00271 FIG. 2 represents mean plasma noribgaine g1ucuronide concern ationie proie after single oral 30 or 60 mg doses, [00281 FIG. 3 rirents mean noribogaine concentration-tirne profile in opioid-addicted patients afer si oral 60 mg dose of noribogaine (gray diamonds). Nean noribogaine concentration-tirne profile in opioid-addicted patients after single oral 120 mg dose of noribogaine (black squares) was estimated based on -valnes for patients recei ing 60 m g dose. 100291 FIG. 4A represents hours to resumption of opioid substitution treat in padteats given no treatmernt (light gray bar), or a snge dose ofrnoribogaine or placebo (60 mg, dark gray bar; 120 ing. black bar). Error bars represent standard deviation [00301 FIG. 4B represents the estimated serum noribogaine concentration in ng/ml at time of resumption of opioid substitution treatment (OST) in patients receiving single oral 60 mg dose of noribogaine (gray diamonds) or single oratl 120 tug dose of noribogaine (black squares). 10031] FIG. SA represents hours to resumption of opioid substitution treatment in patients given no treatment (light gray bar), o a single 120 mg dose of noribogaine (black bar). Error bars represent standard deviation. [00321 FIG, 5B represents the estimated serum noribogaie concentration in ngrml at time of resumption of opioid substitution treatment (OST) in patients recervtng single oral 120 mog dose of noribogaine (black squares). DETAILED DESCRIPTION [00331 The disclosure provides a method to administer noribogaine to a human patient having drug addiction in dosages that provide efficacy without leading to an significant deleterious clinical signs. Such dosages provide maximum serun concentrations (C ) of noribogaine of less than about 2000 ng/mL., while maintaining efficacious average nortibogaine serum levels of between about 100-1 100 n /il (AUC/24 hr).

WO 2014/144508 PCT/US2014/028946 100341 The term "noribaine'' as used herein, refers to noribogaine as wvell as its pharnceuieally acceptable salts. In sonie emiibodiments, the methods of the present disclosure, entail the administration of a prodrup of noribogaine that provides the desired maximum serum concentrations and effleacions aerae in ribogTaine serum levels. A prodrug of noribogaine refers to a compound that metabolizes. n ivio, to noribogaine. In somne embodiment, the prodrug is selected to be readily cleavable either by a cleavable sinking arm or by cleavage of the prodrug cntit that binds to noribo gaine such that noribogaine is gueeated in vvo. in one preferred emhodiment, the prodrug inoiety is selected to facilitate hinding to the u and/or K receptors in the brain either by facilitating passage across the blood rain harrier or by targeting brain receptors other than the p and/or K receptors, Examples of prodrugs of noribogaine are provided in tited States Patent Application Serial No. 13/165626, the content of which is incorporated here by reference. [00351 The following ranges are obtained front a single dose of noribopaine HIl/ fasting patient. [00361 In certain ernbodimrents, the dosages administered provide a Cma of noribogaine of less than about 1980 ng/nL serum and an average AUC/24 hr of about 11 00 ng/mL. In certain embodiments, the dosages administered provide a C, of noribogaine of less than about 1800 ng/mti. serurn and an AUC/24 hr of about 1000 ng/mL. In certain embodiments, the dosages administered provide a Cm, of noribogaine of less than about 1620 ng/L serum and an AUC/24 hr of about 900 ng/mL. In certain embodiments, the dosages administered provide a Cm. of noribogaine of less than about 1440 ng/ml, se-rm and an ALC/24 hr of about 800 ng/'ml., In certain enbodiments, the dosages administered provide a Cm;j of noribogaine of less than about 1260 g/miL serum and an A UC24 hr of about 700 ng/mL.. In certain embodiments, the dosages administered provide a Cmax of noribogaine of less than about 1400 ng/mL. serum and an AUC/24 hr of from about 600 ng/mL. in certain embi odim ent s, the dosagees adm iister ed provide a Co, . of noribogaine of less than about 90t0 ng/mL serum and an AUC/24 hr of about 500 ng/mdL_ In certain embodiments, the dosaesi administered provide a C, of i noribogaine of less than about 720 np ingI serum and an AUC/24 hr of about 400 ng/mL. In certain embodiments, the dosage n administered provide a C.. of noribogaine of less than about 540 ng/mni serum and an AUC/24 hr of about 300 ng/m. In certain embodiments, the dosages administered provide a Cm.I. of noribogaine of ines than about 360 Pgml. serum and an A. UC24 hr of about 200 ig/mL. in certain 6 WO 2014/144508 PCT/US2014/028946 embdiients, the dsaces administced provide a C, of noribogaine of tess than about I 80 ng/mL serunm and an AUC/24 hr of about 100 ng mL.. [003/ In soe eibodi rents such concentrations are obtained by administering from about 100 to about 1 100 mg at intern als of about 24 hours. In some embodiments such concentrations are obtained by administering from about 200 m to about I ,100 ng at inrals of about 24 hours. In some embodiments such concentrations are obtained by administering from about 300 mg to about A00 mg at itmervals of about 24 hours. In sorne embodiments such concentrations are obtained by administering from about 400 mg to about 1 100 ing at intervals of about 24 hours. in some embodiments such concentrations are obtained by administering Rom about 500 mg to about ,I(0 ng at intervals of about 24 hours. In some embodiments such concentrations are obtained by administering from about 600 rug to about 1,100 mg at intervals of about 24 hours. In some embodiments such concentrations are obtained by adrninistering roin about 700 mng to about 1,100 mg at intervals of about 24 hours. In some embodiments such concentrations are obtained by administering from about 800 ing to about 1,100 mg at intervals of about 24 hours. in sore embodinents such concentrations are obtained by admtinistering frorn about 900 mg to about 1,100 mg at intervals of about 24 hours. In some embodiments such concentrations are obtained by administering from about 1,000 mg to about 1 ,100 mug at intervals of about 24 hours. [00381 In some embodiments such concentrations are obtained by adminstering from about 100 mg to about 1,100 mg at intervals of about 24 hours. In some embodiments such concentrations are obtained by administering from about 100 mg to about 1,000 mg at intervals of about 24 hours. In some embodiments such concentrations are obtained by administering from about 100 mcg to about 900 mg at intervals oaf about 24 hours, In some embodiments such concentrations are obtained by administering from about 100 ing to about 800 mg at intervals of about 24 hours. In some embodiments such concentrations are obtained by administering from about 100 mg to about 700 mng at intervals of about 24 hours. In some embodiments such concentrations are obtained by adniiistering from about 1,00 rn to about 600 mg at intervals of about 24 hours. in some embodiments such concentrations are obtained by administering from about 100 mg to about 500 mg at intervals of about 24 hours. In some embodiments such concentrations are obtained by administering from about 100 mg to about 400 mg at itervals of about 24 hours. In some embodiments such concentrations 7 WO 2014/144508 PCT/US2014/028946 are obtaied by adminusterin from about i00 mg to about 300 rg at intervals of about 24 hours. In some embodiments such concentration av obtaiied by adinistering from about D00 mg to about 200 ig at itervals of about 24 hours. 100391 PartiNuary preferred embdimets include the follow ing dose ranges. In sone embodiments each patient is administered from about 100 ; mg to about 600 m at intera Is of about 24 hours. In some embodiments each patient is administered from about 100 m ng to about 500 mg at intervals of about 24 hours, In some embodiments each patient is administered from about 100 mg to about 400 rng at intervals of about 24 hours. In somc embodiments each patient is administered from about 100 mg to about 300 mg at intervals of about 24 hours. In sonie embodiments each patient is administered from about 100 rmg to about 200 mg at iWnervals of about 24 hours. in some embodiments each patient is administered firom about 200 mg to about 600 rug at intervals of about 24 hours. in some embodiments each patient is administered from about 200 rmg to about 500 mg at intervals of about 24 hours. In some embodiments each patient is administered from about 200 mg to about 400 tmg at intervals of about 24 hours. In some embodiments each patient is administered from about 200 tug to about 400 mg at intervals of about 24 hours. In some embodiments each patient is administered from about 200 ng to about 300 mrig at intcrvals of about 24 hours. In some embodiments each patient is administered from about 300 rag to about 400 nig at intervals of about 24 hours. In some embodiments each patient is administered from about 300 mug to about 500 ig at intervals of about 24 hours, In some embodiments each patient is administered from about 300 me to about 600 tmg at intervals of about 24 hours. In some embodiments each patient is administered from about 400 nig to about 500 mg at intervals of about 24 hours. In some embodiments each patient is administered frorn about 400 mg to about 600 nig at intervals of about 24 hours. in somie embodiments each patient is administered from about 500 mig to about 600 tmg at intervals of about 24 hours. 10040] In some embodiments. the patient is administered periodically y, such as once, tw ice, three time, tour times or five tine daily with noribogaine or its prodrug. in some emboiments. the administraton is once daily, or once every second day, once every third day, three times a week. twice a week, or once a week The dosage and frequency of the administration depends on the route of administration, content of composition, age and body 8 WO 2014/144508 PCT/US2014/028946 we cight of the patient, c of the patient, wit hout lim*aton. De termi ntion of dage and frquency suitable fbr the pres technology can L readi ade a qoalified clinician. 100411 These dose roaes are achieved by oral or its prodrug which may conveniently be provided in tablet, capet, liquid or capsule form. In certain emho iments. the nobo aine i provided as niogaine iCl., with d reported as the arnount of free base noribogaine. in some embodiments. the niribogaine iCl is provided in hard gelatin capsuics containng only noribogaine HI with no excipients. 00421 Without wishing to he bound by theory, it is believed that noribogaine provides its anti-withdrawal symptom effects by acting as both an u334 nicotinie receptor and a serotonin reuptake blocker acting on the 5-i IT Transporter. [00431 The foloWing Examples are intended to further illustrate certain embodiments of the disclosure and are not intended to limit its scope. Examnpl I Single dose toxicity in rats [0044] T he objective of this study was to determine the toxicity and toxicokinetic profile of noribogaine HCI following a single oral garagee) administration in the Sprague-Daw ley rat. A single dose of 10, 300 and 800 mg/kg (achieved with doses of 400 ng/kg 3 h - 30 min apart because of the limitations of maximum dose fornulation concentration). Five male rats/cronp wre used. Mortality occurred in all male rats in the 800 mg/kg group, approximately 2-3 h after administration of the second dose of 400 i mg/kg. Iypoactivity, vocalization, chewing movements, changes in respiration/posture., slivation, stimuli sensitivity, tremors, twitches and penile erection occurred prior to death. lypoactivity, vocalization, salivation, stimuli sensitivity, loss of limb function and lying on the cage floor occurred on the day of treatment and persisted until Day 2 in 3/5 rats given 300 mg/kg. The low dose rats treated at 100 mg/kg did not show any treatment related signs. The NOAEL was determined to be 100 mg kg. 9 WO 2014/144508 PCT/US2014/028946 K ik le: 1004q In arn : l oral ioxi'c'\ studyt in 10 O i0 fmtality v, u- ofd t (n-2)01 or 10 fri 2 1 ow Qk. Conx dons and other (N~ \ c - I calnil a',n eludin tlcoe saljion calirat Oioncoord-ination and hy'poacti' y. occO Cd at a dose of 10 owy ky. beginning 20( Oinwes Ama chsng and persst n~i 3h 4 i-m post-dose. 'he 55, 1- nse "u s co~nsre Qh NOAiL as only transient reduction in food consumption in onedo owcurren at thatds Example 3 Singledosel i i qv Anoogs Monkeys [00461 The objective of the study w~aso d rnn the toxicity and toxicokinelic profile of noribogaiine iloin oral (gawage) adnainimaton to the cynomol ens m monkey. The is artclewasadr in stredas follows in I'acl 1.: Table 1. '1 oxciy and Tioxicokinetic Stu~dy in Cynomolgws monkeys -1reannent on Situdy Day Dose I-eve, wmgkg) MNumbter of Animnals 2 ) niales 40 2 nales 15 8 and 160 12 Inadles O ne atw "A M rousere 80 mbiJnitku and the other aialas administered 160 mer kg. [10471 LIaran-eters mnitored on the study included: mortality, cliial si'm-ri and body weights. Blood samples -xsere collected for~ Th evauation. No mnortaity o n-eat-nen' related Ankal signs were noted for doses up to and 'ncludin 160 mng/ktg. Th sim, leA dose ruaximum Midmledl dose (MITJ) was te rmir i ndo '-, greater than 1 60 mrg/k-, based on to pa'ues ioni tored during the study., WO 2014/144508 PCT/US2014/028946 Example 4 FournY and toxikineties in rats 100481 iis stdy was conductedO to evalwue the toxicity prfie of noriogainc-Hl follow ig ora ( adinisratin th rat for 1 4 days f ng Table 2 below: Tnbe 2. Toxicit and Toxicokinetic Study in Rats Group Doise Lel nse To-colog Amma-s - -uconeties (mg'g/day) Cocentration Man Rco cry \nmah (mg/mLa Male Female Mae I Female Mal Female rateroup inte0(oto)ad 0 n/k gopweerine fo a 28dyrcvr Nod Dow. 50 61 f 0 19 b) 6 I -I g)' Do se 00n 20 10 50 10U0491 Male and 1'emnale Sproue-Dawley rats, jO/sexYgroup, were administered 0, 25 50 or 00 nwg/k , norihogaine i-IC 1daily by single oral tgava~ge for 14 days. A±n additional 5 rais/sex/wgoupin the 0(control)I and 10O mr/kg gnroups w ere retained for a 28 day recovery period during which no drug was adm-inistered. Six rats/sex/group (3 rats/sex controls) were similarly dosed and sampled on study days I and 14 fOr analysis of noribogaine-HlI concentrations in the blood. Rats were observed for mortality, clinical signs, body weigh, food consumption, ophthalmology (pre-dose, during week 2, and at the end of recovery , hematology, coagulation, clinical chemistry, urinalysis, gross necropsy, organ weightts and histopathology (dld tissue panel plus immunocytoehemistry of 5 sections of the brain and spinal cord by staring for GFAP and Calbindin). There were no test article-related effects on n mortity (none occurred), clinical signs, ophthalmoscopy, hematology, coagulation paramers, cynical chemi tr, urinalysis, gross necropsy or histopathology. Food consu-mption and body weight wee slightly reduced (ood consumption: -4.7% in males and females; body -weight: -5.5% in males and -2.6% in females) in the high dose (100 mg/kg) groups. Minor increases in liver weight in the mid- and high close groups were not correlate with histopathologic changes and are considered incidental. No treatme nt-related differences in the brain were seen in sections stained for GFAP or Calbindin, 100501 The NOAIEL dose in this study was interpreted to be 100 mg/kg, the highest dose tesed in the study. :11 WO 2014/144508 PCT/US2014/028946 Example 5 Forendyrpa dose toxicty and toxicokinetics n dog [00511 T he obective of this study wx as to determine the toxicity profl of noribogaine HCI given foloAiM ora savagee) administration to dogs for 14 days according to the following Table 3 below Table 3. Toxicity and Toxicokinctic Study in Dogs Group Oe I To'nintls Desgnaion (mgkg/dav) -(g/m) Mal e Femae - l- h-mae --tr --- 0 0 4 4 -- -- -- -- -- -- ------------ [00521 Noibogane HC Cws administered to groups of - male and 4 female dogs by single oral gavage daily for 14 days at doses of 0. 0. LO and 5.i mg/kg/day. An additional group of 4 male and 4 female dogs received either the vehicle control or 5.0 i/kg/day for 14 days and were held for an additional 28 days afer cessation of dosing to assess recovery from any potential drug-induced changes. Th stu y was conducted under GLP guidelines and included comprehensive examinations of clinical signs, body weight, clinical pathology parameters, opthalinologiec examinations. EC recordings and analyses of plasma for bioanalytical measurement of drug levels at appropriate intervals during the study. At the termination of the dosing phase and at the termination of the recovery phase, all dogs were subjcted to a complete post-iortem examination including gross exaination of najor organs and histologic examination of an extensive list of tissues. Additional sections of brain were obtained from cerebrum, cerebellus, brain sten and spinal cord and examined histologically to evaluate potential effects on brain histopathology. In addition, these sections were examined wIth inummnohistochemical stains fr GF\P for evidence of glAosi and Calbindin for a more. comprehensive examination of cerebellar Purinje cells No evidence of advrse effect was observed in any dog fron any treated group during the losing or re phase in clinical observations body weights, clinical pat hologcal parameter, ophnhalmologic examinations, E CG recordings, or gross lesions at necropsy. The results of the plasma drug level measurements at Day I and Day 14 of the study are shown in Tables 4 and 5 below. Noribogaine-HI. maximum plasma concentrations (C) were reached between .5 and 0.9 hours post-dosing, soloing which plasma concentrations gradually decreased oxr a period 12 WO 2014/144508 PCT/US2014/028946 of Up to 24 hour, except in the mae dos and nale dogs of Grup 4, for which igi 1cant levels of noribogaine were still detected at 24 h pos dosing on both Days i and 14. 100531 The onli target tissue identified in this study was the lacrmal gland of dogs receive ing- 5 m kg/day. The lacrinal gland changes were characterized by slight to moderate atrophy and degeneration of the acinar cells accompanied by sligt to moderate accumulation of brown Y ello pigmnct and intiHration of mononuclear cells. Here was an associated rononuclear infiltration in the draining nandihular lyrnph nodes of affected dogs in ths dose g roup. Despite the appearance of isolated oculr abnormalities in several dogs in this high dose group on ophtlhalnologic examination. there was no clear association between these ocular signs and the appearance of the lacrinal gland changes su testing that these morphologic changes did not result in sufficient functional abnormality of the gland to produce physical changes in exterior structures of the eye. There was no clear evidence of local irritation associated with drug treatment in these high dose dogs. No evidence of drug induced effect was observed in any other tissue including the extensive sections of brain evaluated wi conventmonal histopathology or whit immunohistochemistry Eaminaton the animals in the recovery group slhowxed clear evidence of regeneration of this lacriimnal gland change. While slight atrophy was still evident in the acinar cells of the gland ater 28 days off drug, no evidence of continuing and ongoing degeneration or cellular infiltration was observed. The NOAEL in this study was I mg/kg/day based on the lacrimal gland changes at 5 mg/kg/day. The results are summarized in Tables 4 and 5. Table 4. Mean plasma toxicokinetic parameters for noribogaine in male (logs on days 1 and 14 Gr- 2 05 mg/kg Gr3 - 1 0 mg/kg Gr 4- 5.t ogkg Paramneters D D14 D/ D/4 DI D14 Tint h) 1 1.3 1U2 1.8 47 6.5 0. .8 .6 0,9 Cm.2ng128.8 r,9 4 . 67.6 693 716 AUM gas (hr*g m 2 46. 53 2 1025 172 3 3515 0 64053 AU (mt) 5 64 5 1198 210.4 3515 6403.3 BTh m n_ _ 28 _ , 120 9 19 5 6961.4 Table 5. Mea N plsia toxicakineic parameters for Inoribogaie in female dogs oil days I and 14 13 WO 2014/144508 PCT/US2014/028946 Gr 2 -- 05 mg/kg Gr 3 - 10 mg/kg Gr 4 - 5.0 mgkg D0 14 D1 D 14 Di D14 T[0 b)21 1.'1 1.4 16 43 57 T-n (br 0.5 1.0 0 .8 0 5 0 6 M Crngml 2 3 29.8 68.5 74 1 69_G1 _683 AU wbr* gm) 315 354 148.9 169.0 3367.9 59512 A m (hr-n -4/m ) 40.4 550 12 20367 91 2 44,9C 4507 1 .. 165. 19 . 3425.7 Example 6 Human Pharmacokinetic studies [0054) In double blind studies fastingi healthym vluneers (6 per cohort ) were treated once orally with a tablet o Unoribogine -CL in escalating cohorts. the volunteers received 3 mg, 10 rng, 30 mg or 6 0 ig noribogaine. The results are provided below. All parameters were linear and no clinically relevant adverse effects were observed in the trial. [0055] The subject mean serurm levels over tine of noribogaine ree base from a single dose of 3 mg noribogaine free base under fasting conditions were plotted. The mean Cm, of 5.2 ng/ml was observed 1.9 hours aner administration, while the mean AUC/24 hr ofl 3.1 ngl n was obtained. [0056) The subject mean serum levels over tine of noribogaine free base from a single dose of 10 mg noribogaine i-ee base under fasting conditions were plotted. The mean m of 14.5 ng/m was observed 2.9 hours after administration, while the mean AUC/24 hr of 10.6 ng/mi was obtained. [00571 The subject mean serum levels over time of noribogaine free base from a single dose of30mgnoribogainefre Ibase under fasting conditions were ploted. The nan Q, of 5.9 ng/ml wuas observed between 1.75 hours after administration. while the mean A tX24 oF 292 ng/mi was obtained. [00581 The subject nean serum icvels over time of noribogaine free base front a single dose of 60 mg noribogaine free base under fasting conditions were plotted. The mean Cmn of 116 ng/i wasobserved between 1.75 hours after administration, while the mean AUC/24 ng/ml of 61 was obtained. I0059 The subjc aean serum levels over t ime of noi b gaine free base for all 4 coIorts were plotted. The exrapolated dosage of noribogaine free base required to provide a Cm 14 WO 2014/144508 PCT/US2014/028946 ranging rn about 53.2 ntgml o about 19 g m and an Al I 2 hr of abo 3.1 n m to about 1100) u, nl was determined. Example 7 Piarmacokinetics and pharmacodynamies of noribogaine in humans 100601 Thirty-six healthy, dru-free male volinters, aged between 18-55 years. were enrolled in and completed the study, i 1 s was an ascending single-dose, placebo-controlled, randomised double blind, parallel group study. Mean (SD) age was 22.0 (3.3) years, mean (SD) height was 1.82 (0,08) m, and mean SD)) weight was 78.0 (9,2) kg. Twenty-six subjects were Caucasian,. 3 were Asian, I Maori, I Pacific Islander and 5 Other Te protocol Oar this study was approved by the I.ower Suth Regional Ethics Comnit tee (L RS/1206i/015), and the study was registred with the Australian New Zealand Clinical Trial Registry (ACTRN1 2612000821897). All subjects provided signed inforned consent prior to enrollment, and were assessed as suitable to participate based on review of medical history, physical examination, safety laboratory tests, vital signs and ECG. [0061] Within each dose level, 6 participants were raidomized to receive noribogaine and 3 to receive placebo, based on a computer-generated random code. Dosing bean with the lowest noribogaine dose. and subsequent cohorts received the next highest dose afler the safety, tolerabilty, and blinded pharmacokinetics of the completed cohort were revicwed and dose-escalation approved by an independent Data Safety Monitoring Board. Blinded study drug was administered as a capsule with 240 ml of water after an overnight fast ofat least 10 hours Participants did not receive any food until at least 5 hours post-dose. Participants were confined to the study site from 12 hours prior to drug administration, until 72 hours post dose, and there were subsequent outpatient assessments until 216 hours post-dose. 100621 Blood was obtained for pharmacokinetic assessments pre-dose and then at t.25, 0.5, 075, 1.0, 1.25, 1.K2. 2, 3. 3, 3.4, 4.5. 5, 5., 6, 7, 8, 10, 2. 14, 18, 24, 30. 36. 48. 60, 72, 96, 120, 168 and 216 hours post-dose Samples were centrifuged and plasma stored at -70 'C until anaz 1ed. Block 24 hour urine collections were obtained following study drug administration for the 30 and 60 mg cohorts. Aliquots were frozen at -20 C until analyzed. [0063] Pulse oxietry and capnography data were collected continuously using a GE Carescape 13650 monitoring system from 2 hours prior to dosing and until six hours after dosing, and thereafter at 12. 24, 48 and 72 hows pos-dos ing. Additional oietry data were 15 WO 2014/144508 PCT/US2014/028946 collected at 120, 168 and 216 hour. Pupill ar niosis -as assessed by puil lometry. Dark-, adapted pupil dimetrc was measured in triplicate using a Neuroptics PLR-200 pupillotner under standardized ligt intensiy (5 lux) pre-se, and at 2, 4, 6, 12, 24, 48, 72, 96, 120, 168 and 216 house post-dosing. [00641 Plasia noribogaine concentrations were determined in the 3nmg and 10 mg dose groups using a validated, sensitive LCM'- SMS imethodS p ation involved dobl extraction of basified pasma samples with tert-butyl methyl e there, drying he samples under a streamn of nitrogen and reconsttution of sample -with acetonitrile:B.P. water (5:95, v/v) containing 0.1% (v/v) formic acid. The compounds -were separated by a 150 X 2.0 mn Luna 5un C18 column and detected with a triple - quadrupole API 4000 or 5000 mass spectrometer using electrospray ionizaion in positive mode and multiple reaction monitoring. Noribogaine-di was used as the intemal standard. The precursor-product ion transition values for noribogaine were m/z 297 6 -> 122.3, and for the internal standard noi/bogaine-d iz 301 .1 -> 122.2. Analysts software was used Or data acquisition aniid processing. The ratio of the peak area of noribogaine to the iMernal standard noribogaine- 1 was used for calibration and measurement of the unknown concentration of noribogaine. The lower timi of quantdication (L LOQ) was 0.025 ng/mi rnoribogaine. The calibration curve was between 0.025 and 25600 ng/ml noribogaine. Mobile phase A was acetonitrile:B.P. water (5:95, v/v) containing 0.1% (v/v) formic acid, and mobile phase B was acetonitrile:B.P. water (95:5, v/v) containing 0.1% (v/v) formic acid. Total run time was 6 minutes. Binary flow: Initial concentration was 8% mobile pihase B; hold at 8% mobile phase B for 0.5 milnIes and linear rise to 901% mobile phase 1B over 1.5 minutes: hold at 90% mobile phase B tor minute and then drop back to 8% mobile phase B over 0.01 minute. Equilibrate system fbr 3 minutes. Total run time was 6 minutes. Within- and between-day assay precision was < 9%, and within- and between-day assay accuracy was < 9%. [0065] Plasma noribogaine concentrations were determined in the 30 mg and 60 mg dose groups using a validated, sensitive LCMIISMS method. Sample preparation involved deproteinization of plasma samples wx ith acetonitrile and dilution of sample wih % I v formiic acid. The compounds were separated by a 150 x2.4 mrin ILna 5pm 1 8 column amd detected with a triple - quadrupole API 4000 or 5000 mass spectrometer using electrospray ionization in positive mode and multiple reaction monitoring. Noribogaine-d was used as the internal standard. The precursor-product ion transition values for norib gaine were m 29.T6 - 122.3, and for the internal standard noribogainc-d14 m/z 301 .1 -> 122.2. Analyst" solftwvare 16 WO 2014/144508 PCT/US2014/028946 was used for data acquisition and processing. I he ratio of the peak area of noribogaine to thie internal standard n rihogai -d was used for calilbration nd vieasurement of the unknown concentration of noribogaine. The L LOQ was 0.50 ng/ml noribo aie. The calibration curke was between .0 avid 256.00vi nminoribogaive. Mobide phase was the same as method A, and biiary flow was also the same as method A. The within- and between-day assay precision as <9 and the within.- and betwveen-day assay accuracy w as< 91. [0066] Plasma noribogaine glucurionide concentrations wvere determined in t 0e 3mgu and 60 ng dose groups using a validated senstive LCMSSI method. Sample preparation ilvx ed deproteinization of plasma samples wvith acetonitrile. drying the samples under a streak of nitrogen and reconstitution of sample xwith acetonitrile:B.P. water (5:95, v/v) containing 0. 1%0 (v/v) formic acid. The compounds were separated by a 150 x 2.0 mm Luna 5nm CO 8 column and detected with a triple - quadrupole API 4000 or 5000 mass spectrometer using electrospray ionization in positive mode and multiple reaction monitoring. Noribogaine-d4 was used as the internal standard. The precursor-produet ion transition values for noribogaine giucuronide were im/z 472.8 -> 297-. and for the internal standard noribogaine-d i/z 301.1 -> 122.2. Analyst) sofitware was used for data acquisition and processing. The ratio of the peak area of noribogaine gl1ucuronide to the internal standard noribogaine-d was used fOr calibration and measurement of the unknown concentration of noribogaine glucuronde. Ihe LIOQ was 0.050 ng/mn noribogaine glucuronide. The calibration curve was between 0.050 and 6,400 ng/ml noribogaine glucuronide. Mobile phases was the same as method A. Blinary flow: Initial concentration was 6% mobile phase B; hold at 6% mobile phase B for 0.5 minutes and linear rise to 90%O mobile phase B over 2 minutes; hold at 90% mobile phase B for I miAnue and then drop back to 6' mobile phase B over 0.01 minute. Equilibrate system fbr 3.5 mnutes. Total run time was 7 minutes. 'Ie within- and between-day assay precision was < 11%, and the within- and between-day assay accuracy was <- 0. 10067] Urine noribogaine and noribogaine glucuronide concentrations were determined in the 30 mg and 60 mg dose groups using a valiated sensitive LCMSMS method. Sampe preparation involved deproteinization of urine samples ith acetonitrile and dilution of the saniple with 0.1%K. (v/v) formic acid. The compounds we re separated by a i50 2.01 mmi Lnan 5pmn C1t8 column and detected with a triple - uadruipole API 5000Y mass spctr ometer usig electrospray ionization in positive mode and multiple reaction monitoing Noribogaine-d4 was used as the internal standard, The precuirsor-product ion transition values for noribogaine 17 WO 2014/144508 PCT/US2014/028946 were m/z 2976 -> 122.3, noribogaine glucuronide m/z 4T2.8 - 297.3, and for the intemai stndr noribogaine-dIa / 301.1 -> 122.. Analy" s . otwa as used tor data acquisitn and processing. The ratios of the peak area of nribogame and nribogaineic gILucurotide to thte internal standard norbogaine-d4 were used for calihration and measrcrnent of the unkIon concentration of noribogaine and its glucuronide. Assay LOQ was 20.0 ng ml for noribogainc and 2.0 ng/rl for noribogaine glueronide. The calibration curve was bet wen 20.0 and 5120. nr noribogaine, and 2.0 and 512.0 ng/ml noribogaine glucuronide. Mobile phases were as described in method A, and binary flow as in method C. IThe with in and between-day assay precision was < 3% .and within- and betwneen-day assay acc Ira was < 12%. 100681 Noribogaine and noribogaine glucuronide concentrations above the limit of quantification were used to calculate pharmacokinetic parameters using model-indepsendent methods. The maximum plasma concentration (Cmax) and tirne to maximumin plasma concentration (Tmax) were the observed values. Plasma concentration data in the post distribution phase of the plasma concentration-time plot were fitted using linear regression to the formula In C i hn Co - Kel, where Co was the zero-tine intercept ofl the extrapolated terminal phase and Kel was the terminal elimination rate constant. The halftlife (tA) was determined using the formula t 1 = 0.693/Kel. The area under the concentration-time curve (A UC) from time zero to the last determined concentration-time point (tfi in the post distribution phase was calculated using the trapezoidal rule. The area under the curve from the last concentration-irne point in the post distribution phase (Ct-) to time infinity was calculated from AJC.= Ctf/Kel. The concentration used for Ctf was the last deernined value above the LLOQ at the time point. The total AUCo. was obtained by adding AUCQ and AUC, Noribogaine apparent clearance (CU) w as determined using the tfula CL = Dose/AtCm. x 1000, and apparent volume of distribution (Vd/F) was determined ustig the forrnula Vd/= (CL / FKel Total urine noribogaine was the sum ol both analytes. [00691 Sumunary statistics (means standard deviations, and coefficients of variation) were determined tor each dose group for safety laboratory test data, ECG-i and pharmacokinetic parameters, and pharmacody namic variables. Categorical variables were analysed using counts and percentages. Dose-proportionality of A UC and Cnax was assessed using linear regression. The effect of dose on phamacodynamic parameter values over time was assessed usingc two- factor analysis of variance (ANOVA). Pairwise comparisons (iith Tlukey -K raner 183 WO 2014/144508 PCT/US2014/028946 adjustment) between each dose group to the placebo wk ere conducted at each time point using the oet squares estimtes obtained from the ANOVA, using SAS Proc Mixed (SAS ver 6.0). Results [00701 Plharmacokinetics: Mean plasma concentration-time Alots of norioaine are s hon a in Figure 1. and rean pharnmacokinetic parameters are shonn Table 6. Table 6 3 m 1 t- 10 mg (n=6) 30 m- - n i Norhoaie n' auSDp (mean (SD)) (mean (SD)) (mean (SD) 74.2 (13.1) 254.5 (7 8

.

9 ) 700K4 (223.3) 1962 2 (726.5) 722 (13.2) 251.4 (78.5) 6776 (221.1) 19354 (7254 524. (2.] 55.9 (148) 116,0 (22.5) (n2 n 6 Im-- n (-- 19 '(0-- t 2.9 (18) 1.8 (0.6) 2 (0.6) e thi __ 40.9 (a.7) 49,2 (11.5) 27.6 (7.0)) 29.1 (93 \0- dId ( (801 3085 8 (11 97.0 0 14168 (670.1) _t A) 4 (7.) 2 (2.0) 469 (164) 34 - 4) uoio nc tueuronide .................................. ............... 258 (9.3) 6.1 2 1) -. r/ 1 -~ -_ _ _ _ _ -- --- --------- 25.7 (9.1) 650 (2 5) -1.8(0.6) 4.1 (1.2) Tmax (hr 3. -- 0----0(06) 3.8 (1.2 (br) 20A (.6(4.

9 ) 23.10) 10071] Noribogaine was rapidly absorbed, with peak concentrations occurring 2-3 hours after oral dosing. Fluctuations in individual distribution-phase concentration-tirne profiles may suggest the possibility of enterohepatic recirculation (see highlighted individual 4-8 hour profiles in Figure 1, insert). Both (ax and AUC increased linearly with dose (Table 6, upper panel). Mean half- ife estimates of 28-50 hours were observed across dose groups fOr noribogaime% Volume of distribution was extensive (1,411 7-3086 L across dose groups). 100721 Mean plasma noribogaine giucuronide concentration-time plots for the 30 mg and 60 mg dose group are shown in Figue 2. and mean pharnacokinetic parameters are shown in Table 6, lower panel. Noribogaine glucuronide was detected in all subjects by 0.75 hours. with peak concentrations occurring 3-4 hours after noribogaine dosing. Mean half-life of 21 19 WO 2014/144508 PCT/US2014/028946 23 hours was estimated or plasma noribogane gluurnide. The proportion of noribogaine luc uonide Cmax and AUC relative to noribogaine as 3-4% for both dose groups. I oal urine noribgaine eliminlat k ion was 1. 6 mg and 0.82 mg for the 30 mg and 60 mg dose groups respeci vely representing 3.9% and 1 .4% of the doses administered. 100731 Pharmacodynamics: There was no evidence of pupillary constriction in subjects dosed faith noribogaine, No between-dose group differences in pupil diameter were detc over time. After adjusting for baseline difTfences, comparison of each dose group with placebo by ANOVA showed no statistically significant differences (p>0.9). 100741 Noribogaine treatment showed no analgesic efct in the cold pressor test. Analgesic effect was assessed based on duration of hand immersion in ice water and on visual analog scale (VAS) pain scores upon hand removal from the w after bath. For duration of hand inmersion. after adjusting fOr baseline dillerences, comparison of each dose group with placebo by ANOVA showed no statistically significant differences (p>0.9). Similarly, for VAS pain scores. after adjusting for baseline diflfrences, comparison of each dose group With placebo by ANOV A showed no statistically significant differences (p:0.17). Exanplc 8 Safety and tolerability of noribogaine in humans [00751 Safet and tolerabilit of noribogaine were tested in the group of volunteers from Example 1. Cold pressor sting was conducted in 1 C water according to the method of itchell et al, (J Pn 5:233-237. 2004) pre-dose, 6, 24, 48, 72 and 216 hours post-dosing. Safety evaluations included clinical monitoring, recording of adverse events (A Es), safety laboratory tests, vital signs, E G telemetry from -2h to 6h after dosing, and 12-lead electrocardiograms (ECGs) up to 216 hours post-dosing. Results 100761 A total of hirteen adverse events were reported by seven participants (Table 7). Six ad erse events were reported by three participants in the placebo group, five adverse events were reported by two subjects in the 3 mg dose group, and one adverse event was reported by single sub jects in the 10 ng and 30 ig dose groups, respect ively. The most common adv erase events were headache (four reports) and epistaxis (two reports). All adverse events were of mild-moderate intensity, and all resolved prior to study completion here were no changes in vital signs or safety laboratory tests of note. In particular, there r no changes in oximetry or capnograph. or changes in respiratory rate. There were no Q f' values>500 nsec at any 20 WO 2014/144508 PCT/US2014/028946 time. One subject doed w ith 10 ng toribogaine had a single increase in Q'Icf of>60 msec at 24 lous pos-dosing. Table 7 D~ose Mild Moderate \emecr m Ml Placebo Blephar is' Episaxis Bruising Drv Skin Eye pain, nonspecn h tsit Infection at cannuja site Back pain Headache DLzzness Epitais Headache 10 Headache - 30 Headache EXAMPLE 9 Efficacy of noribogaine in humans [00771 T he efficacy o no ribogaine in h humans was evaluated in opioid-depen ent participants in a randomized, placeb-cotrolled, double-blind al In the first cohort, six patients were orally administered a single dose of 60 img noribogaine, and three parents received placebo. In the second cohort, five patients were oraHy administered a single dose of 120 mg noribogaine. and three patients received placebo. Treatment wvas administered 2 hours afer last morphine dose and the time to resumption of rnorphine (opioid substitution treatment, OST) was determined. No adverse effects of noribogaine were observed in any of the participants. i-ncluding no hallucinatory eflfcts. 100781 Fi gure 3 indicates the serum noribogaine concentration over tim-ie. Serum concentrations for 120 ing dose (black squares) are estimated based on data trom the 60 ng dose (gray diamonds) Blinded Results 10079] Patients in the first cohort exhibited an average time to resumpion of opioids after treatment nith 60 mg noribogaine or placebo of approximately 8.7 hours, which is almost 2 21 WO 2014/144508 PCT/US2014/028946 hours longer than that reported fOr untreated itients n a similar study Patients in the second cohort exhibited an avenrage te to resuniption of upioids afer treatment ith 120 ing noribogaine or placb'o of approxitaely 23 hours. Figure 4A indicates the a erage tme to resumption of orphine for control untreatedd, light gra bar), irst cohort (dark gray bar) and second cohrt i black bar). Mean prolongation of the QT inters A n a less than 10 ins for pat ients in the first cohort and was les than 40 ms in the second cohort. [00801 Figure 4B indicates the estimated noriboaine concentration (based on tuhe data frorn Figure 3) a the time of resumption of morphine for each patient. 10081] Although the study was blinded, the patients in the second cohort ws ho received placebo were cunstrued to be those patients exhibiting no prolongation of the QT interval. The average time to resurption of OST for the remaining five patients was determined to be approximately 26.8 hours, as indicated in Figure 5A (black bar), Figure 5B3 indicates the estimated noribogaine concentration (based on the data from Figure 3) at the time of resunmtion of morphine for each (presurned) noribogaine-treated patient. 22

Claims

1. A method for treatg withdrawA syptoms in a patient suffeng from withdrawrA from Addicton to a substance cornsn a dinLstering to the paint a dosage of nboi that provides a Cax of norian of less than about 1980 ng/m serum and in i qc AUC/24 hr of about I ,0 ngr nl.

2. A method fr eating withdrawal symptoms in a patient sufferin fon w hdr in al from addiction to a substance comprising adminisering to the pat ient a dosage of noibogaine that provides a Cmax of noribogaine of less than about 1800 ng/mg serum and an AUC/24 'nr of about 1000 ng/ml.

3. A method for ti ing withdrawal symptoms in a patient suffering from withdrawal ron addiction to a substance comprising administering to the patient a dosage of noNibo that provides a Cma of noribogaine of less than about 1620 ng/mg serum and an AUC/24 hr of about 900 ng/mL.

4. A method for treating withdrawal symptoms in a patient suffkring from withdrawal from addiction to a substance comprising administering to the patient a dosage of noribogaine that provides a C, of noribogaine of less than about 1440 ng/mg serum and an A IUC/24 hr of about 800 ng/rnm. . A method for treating witdr awal symptoms in a patient suffering from withdrawal from addiction to a substance comprising administering to the patient a dosage of noribogaine that provides a Co of noribogaine of less than about 1260 ng/meg serum and an AIC/24 hr of about 700 ng/ni.

6. A method for treating withdrawal symptoms in a patient sufering from withdrawal from addiction to a substance comprising administering to the patient a dosage of noribogaine that provides a C of noribogaine of less than about 1400 ng/mg serum and an AIC/24 hr of from about 600 ng/ml.

7. A method for treating withdai 0 s symptoms in a patient suffering from withdrawal froin addiction to a substance comnpriusing adninistering to thc patient a dosage of noribogaine that provides a C. of noribogaine ofless thfan about 90) ng/mg neum and an Al/f./24 hr of about 500 ng/ml. 23 WO 2014/144508 PCT/US2014/028946

8. A method for treating withdrawal symptoms in a patient so Nlen o n o A ua A from addction to a substance comnpring to the ptnt a dosage of rribogn that provides a C. :of noribogaine of less than about 720 no/rng erum and an AUC/.24 hr of about 400 ynmi

9. A method for treating withdraw al s mptois in a patient uffring from A ithdraa from addiction to a uhstance comprising administering to the patient a dosage of noribogaine that provides a C. of noribogaine of less than about 540 ng/rn serur and an AU C/24 hr of about 300 ng/ml.

10. A method 11o treating withdraw al sImptons in a patient suffenng from widtraa fmm addiction to a substance comprising admnistering to the patient a dosage of nribogane that provides a C noriba aine of less than about 360 ng/mg serurn dt an A t(/4 rof about 200 ng/ml. I1 . A method for treating withdrawal symptoms in a patient suffering from withdrawal from addiction to a substance comprising admnistering to the patient a dosage of noribogaine that provides a C of noribogaine of less than about 180 ng/rmg serum and an AUC/24 hr of about 100 ngml.

12. A method fo treating withdrawal symptorns in a patient suffrintg front wihrawal from addiction to a substance conprising administering to the patient a dosage of noribogaine horn about 100 rog to about 600 mg at intervals of aboit 24 hours,

13. The method according to claim 12, wherein the patient is administered a dosage of noribogaine from about 100 mg to about 500 mg at intervals of about 24 hours. 14, The method according to clairn 12 2.'herein the patient is administered a dosage of noriogaine front about 100 mg to about 4 00 mg at intervals of about 24 hours.

15. Ie method according to clain 12, wherein the patient is administered a dosage of noribogaine from about 100 ng to about 300 mg at intervals of about 24 hours.

16. The method according to claim 12, wherein the patient is administered a dosage of noribogainc ron about 100 mog to about 200 img at intervals of about 24 hours. 24 WO 2014/144508 PCT/US2014/028946

17. A method for treating withdrawal sym ptuoms in a patient suffering fro withdrawal from addiction to a substance comprising adminsern to the patient a dosage ofnoutO ne fnom about 200 mg to about 600 mg at intern al of about 24 hours.

18. The method according to claim 17. wherein the patient is administered a dosage 0f noribogaine frm about 200 mg to about 500 mg at n als of about 24 hours.

19. The method according to claim 17. wherein the patin is administered a dosage of noribogne froin about 200 ng to about 400 mg at intervals of about 24 hours.

20. The method according to claim 17, wherein the patient is administered a dosage of noribogaine from about 200 mg to about 300 mg at intervals of about 24 hours,

21. A method for treating withdrawal symptoms in a patient sufferng trom w itdraw from addiction to a substance compriNsng admisterin to the patient a dosage oft oribogaine from about 300 mg to about 600 mg at intervals of about 24 hours.

22. The method according to claim 21, wherein the patient is administered a dosage of noribogaine firom about 300 mg to about 500 mg at intervals of about 24 hours.

23. The method according to claim 21, wTerein the patient is administered a dosage of noribogaine from about 300 mg to about 400 mg at intervals of about 24 hours, [n some embodiments each patient is administered from about 400 mg to about 500 mg at ite As of about 24 hours.

24. A method far treating withdrawal symptoms in a patient suffiering from withdrawal from addiction to a substance comprisng administeing to the patient a dosage of noribogaine from about 500 mg to about 600 mg at intervals of about 24 hours. 25